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Peer-reviewedCC BY-NCScience Advances

Trans-synaptic interaction of orphan GPCR GPR88 and adhesion GPCR BAI3 through C1ql1 maintains synapse integrity

  • Ying Han1,2
  • Qingbiao Meng3,4
  • Xuan Li3,4
  • Qin Huang1,2
  • Liming Qin1,2
  • Liangyu Liao5,6
  • Ke-Ke Xing7
  • Jie Cheng3,4
  • Lulu Guo3,4
  • Chao Zhang8
  • Tao Chen7
  • Zhiyi Wei5,6,9
3 more authors
  • Xiao Yu3,4
  • Jin-Peng Sun3,4
  • Bo Zhang1,2,10
10 affiliations
  1. 1Institute of Neurological and Psychiatric Disorders, Shenzhen Bay Laboratory, Shenzhen 518132, China.
  2. 2School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen 518055, China.
  3. 3NHC Key Laboratory of Otorhinolaryngology, Qilu Hospital and School of Basic Medical Sciences, Shandong University, Jinan, Shandong 250012, China.
  4. 4Advanced Medical Research Institute, New Cornerstone Science Laboratory, Shandong University, Jinan, Shandong 250012, China.
  5. 5Shenzhen Key Laboratory of Biomolecular Assembling and Regulation, Shenzhen 518055, China.
  6. 6Department of Neuroscience and Brain Research Center, School of Life Sciences, Southern University of Science and Technology, Shenzhen 518055, China.
  7. 7Department of Anatomy and K.K. Leung Brain Research Center, Fourth Military Medical University, Xi’an 710032, China.
  8. 8Institute of Brain Science and Brain-inspired Research, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 250117, China.
  9. 9Institute for Biological Electron Microscopy, Southern University of Science and Technology, Shenzhen 518055, China.
  10. 10Shenzhen Medical Academy of Research and Translation, Shenzhen 518132, China.
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Abstract

GPR88 is an orphan GPCR with genetic variants associated with multiple neuropsychiatric conditions. GPR88 exhibits enriched expression in the striatum, olfactory tubercle, and inferior olive. Despite these functional associations, its endogenous ligand and its downstream molecular pathways remain unresolved. Here, we found that climbing fiber (CF)-localized GPR88 regulates CF-Purkinje cell synapses in the cerebellum and associative learning behaviors. The results support the CF-secreted protein C1ql1 as the ligand of GPR88 and further revealed that C1ql1 activates biased Gq signaling to enhance CF synapses. Last, we demonstrated that GPR88 anchors C1ql1 and, via C1ql1, forms a tripartite complex with the postsynaptic adhesion GPCR BAI3 in vitro. These findings resolve the orphan status of GPR88 and likely reveal a mechanism by which a secreted protein links two GPCRs to fine-tune synaptic signaling at pre- and postsynaptic sites.

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Cite

BibTeXRIS
BibTeX
@article{han2026transsynaptic,
  title = {{Trans-synaptic interaction of orphan GPCR GPR88 and adhesion GPCR BAI3 through C1ql1 maintains synapse integrity}},
  author = {Ying Han and Qingbiao Meng and Xuan Li and Qin Huang and Liming Qin and Liangyu Liao and Ke-Ke Xing and Jie Cheng and Lulu Guo and Chao Zhang and Tao Chen and Zhiyi Wei and Xiao Yu and Jin-Peng Sun and Bo Zhang},
  journal = {Science Advances},
  year = {2026},
  month = oct,
  doi = {10.1126/sciadv.aec0867},
  url = {https://www.science.org/doi/abs/10.1126/sciadv.aec0867},
  note = {CC BY-NC},
}
RIS
TY  - JOUR
TI  - Trans-synaptic interaction of orphan GPCR GPR88 and adhesion GPCR BAI3 through C1ql1 maintains synapse integrity
AU  - Ying Han
AU  - Qingbiao Meng
AU  - Xuan Li
AU  - Qin Huang
AU  - Liming Qin
AU  - Liangyu Liao
AU  - Ke-Ke Xing
AU  - Jie Cheng
AU  - Lulu Guo
AU  - Chao Zhang
AU  - Tao Chen
AU  - Zhiyi Wei
AU  - Xiao Yu
AU  - Jin-Peng Sun
AU  - Bo Zhang
PY  - 2026
DA  - 2026/10/28
JO  - Science Advances
DO  - 10.1126/sciadv.aec0867
UR  - https://www.science.org/doi/abs/10.1126/sciadv.aec0867
AB  - GPR88 is an orphan GPCR with genetic variants associated with multiple neuropsychiatric conditions. GPR88 exhibits enriched expression in the striatum, olfactory tubercle, and inferior olive. Despite these functional associations, its endogenous ligand and its downstream molecular pathways remain unresolved. Here, we found that climbing fiber (CF)-localized GPR88 regulates CF-Purkinje cell synapses in the cerebellum and associative learning behaviors. The results support the CF-secreted protein C1ql1 as the ligand of GPR88 and further revealed that C1ql1 activates biased Gq signaling to enhance CF synapses. Last, we demonstrated that GPR88 anchors C1ql1 and, via C1ql1, forms a tripartite complex with the postsynaptic adhesion GPCR BAI3 in vitro. These findings resolve the orphan status of GPR88 and likely reveal a mechanism by which a secreted protein links two GPCRs to fine-tune synaptic signaling at pre- and postsynaptic sites.
SN  - 2375-2548
ER  -